The central theme of this project is a T2-Relaxation-Under-Spin-Taggin (TRUST) technique for quantitative measurement of venous blood oxygenation. The work in the current cycle has focused on its utility in fMRI normalization. In the next cycle, we will have two research foci. One is to continue our efforts on fMRI normalization and its dissemination (Aim 1). The other is to examine a new utility of TRUST in evaluations of brain oxygen utilization (Aims 2 and 3). Since oxidative metabolism is the predominant mode of energy generation (ATP production) in the brain, the ability to measure brain oxygen utilization on a standard clinical scanner will have a profound impact in many brain disorders. FMRI provides a non-invasive approach to assess brain function and has the potential of broad clinical applications. A main limitation of the current fMRI technique is that the signal is an indirect measurement of neural activity and is influenced by non-neural factors such as vascular properties of the brain. In the current funding cycle, we have shown that fMRI signal can be normalized with a cost-effective approach, by accounting for baseline venous oxygenation measured with a TRUST MRI technique. We further showed the utility of this normalization in better detection of disease effects or medication effects on neural activity. Our next goal is to make this tool benefit the broader scientific community. Therefore, in the next cycle, one of our emphases is the dissemination of the TRUST technique and the associated fMRI normalization method. We will conduct a multi-site study (in Aim 1) by leveraging resources of several other NIH-funded fMRI projects and adding our 1.2-min TRUST protocol to their scan sessions. We will test whether the TRUST technique can provide reliable estimation of venous oxygenation across sites, through which we aim to show that TRUST- based fMRI normalization can benefit a wide spectrum of fMRI studies with relatively little added costs. Aside from its utility in fMRI normalization, the TRUST technique and the associated measure of venous oxygenation can be extended to estimate cerebral metabolic rate of oxygen (CMRO2), a key marker for tissue viability and brain function. The availability of a clinically practical CMRO2 technique will find immediate applications in many disorders, such as neurodegenerative diseases and metabolic syndrome. The other emphasis of the proposed project will therefore be the further development of MRI techniques to allow a quantitative measurement of CMRO2. Aim 2 will focus on a global technique which, although not providing regional values, is expected to be fast (<5 min scan time) and highly reliable (coefficient of variation, CoV < 4%), and its utility in Alzheimer's Disease will be examined. Aim 3 will further push the envelope of technology by focusing on the development and validation of a novel pulse sequence, T2-Relaxation-Under-Phase- Contrast (TRU-PC) MRI, which provides a regional estimation of oxygenation and CMRO2.